PROJECT 3 ? SUMMARY/ABSTRACT Epstein-Barr Virus (EBV) and Kaposi's Sarcoma Herpesvirus (KSHV) cause lymphomas, carcinomas, and sarcomas in people across the world. No specific anti-viral therapies or vaccines are available now to treat these tumors or to prevent infections with EBV or KSHV. During the current funding period, we have developed new technologies and used them to uncover exciting discoveries about entry into and progression through the productive or lytic phase of the life-cycle of EBV. We have developed live-cell imaging of intact, infectious genomes of EBV and KSHV and found that during its lytic cycle EBV amplifies its DNA in discrete sites or factories, mediates a dramatic concentration of cellular chromatin at the nuclear periphery, and inhibits synthesis of histone chaperones. We have also found that this amplified viral DNA lacks histones and is the template for viral late gene transcription. We shall examine at the single cell level the formation of both EBV's and KSHV's amplification factories, their consolidation of cellular chromatin, and their mechanisms of transcription of viral late genes in these factories. These detailed studies will identify virus-specific processes that can be targeted to block virus spread.